A unique vaccine platform employs novel bioengineerable nanoparticles, Haloarchaeal gas vesicles (HGVs), as an adjuvant and antigen delivery system that is inexpensive, effective, and shelf-stable (requiring no refrigeration). When administered to animals, HGV nanoparticles with surface-displayed antigens produce strong long-lived immune responses. In previous work, antigens from bacterial and viral pathogens were expressed as a fusion to one of the HGV protein components and in all cases the recombinant HGVs were highly immunogenic in mice. We plan to test the effectiveness of HGVs as a vaccine vehicle against Salmonella enterica serovar Typhi, the causative agent of typhoid fever. These human pathogens remain important causes of morbidity and mortality in many countries as a result of poor sanitation, and water and food contaminated by human fecal waste. Our goal is to progress toward the development of a safe and inexpensive oral vaccine against invasive Salmonella disease that can be used in both the developing and developed world. We propose to: (a) produce multiple Salmonella protective antigens displayed on HGV nanoparticles; and (b) deliver the bioengineered HGV-vaccine antigen nanoparticles and determine their protective efficacy in a mouse model. We will also perform more in-depth immunological analyses and test protection using combinations of HGV formulations. These studies will lay the foundation for subsequent evaluation of this approach in humans as well as customize the system for prevention of other diseases. The development of a safe, oral adjuvant and vaccine delivery vehicle which is inexpensive, effective, and shelf-stable should lead to a global revolution in the prevention of infectious diseases.